P1270: MYELOABLATIVE FRACTIONATED BUSULFAN-BASED CONDITIONING REGIMEN IN PATIENTS WITH AML AND MDS: RESULTS OF A RANDOMIZED CLINICAL TRIAL COMPARING 2 FRACTIONATION SCHEDULES
Authors: Uday R. Popat, Konstantinos Lontos, Roland Bassett, Jitesh Kawedia, Ben C. Valdez, Alison Gulbis, Amin M. Alousi, Gheath Al-Atrash, Qaiser Bashir, Chitra M. Hosing, Jin S. Im, Partow Kebriaei, Issa Khouri, David Marin, Rohtesh S. Mehta, Yago Nieto, Betul Oran, Amanda Olson, Muzaffar H. Qazilbash, Jeremy L. Ramdial, Neeraj Saini, Samer A. Srour, Tapan Kadia, Naval Daver, Nicholas Short, Katayoun Rezvani, Elizabeth J. Shpall, Richard E. Champlin, Borje S. Andersson
Journal: HemaSphere (2023)

Topic: 22. Stem cell transplantation - Clinical Background: Hematopoietic stem cell transplantation (HSCT) cures leukemias, but comes at a cost of higher toxicity and non-relapse mortality (NRM). We previously showed that fractionating the busulfan (Bu) dose and starting it on day -13 instead of day -6, leads to lower toxicity and permits delivery of a myeloablative regimen, even to older patients. Additional optimization of this fractionation modality may further reduce toxicity and result in improved outcomes in patients undergoing allogeneic HSCT. Aims: Through a single institution randomized trial, we sought to validate the concept of fractionation and to test the hypothesis that further fractionation, by starting chemotherapy on day -20, further reduces toxicity and lowers NRM without increasing relapse risk. Methods: Patients with AML or MDS, 18 to 70 years old, with a matched related or unrelated donor were eligible if they had adequate organ function. Patients were randomized to one of two arms: The shorter arm consisted of outpatient Bu 80mg/m2 on days -13 and -12, while the longer arm consisted of outpatient Bu 80mg/m2 on days -20 and -13. The rest of the regimen and GVHD prophylaxis were similar in both arms: On days -6 to -3, fludarabine 10mg/m2, cladribine 10mg/m2 and Bu dosed to achieve total Bu exposure of 20,000 ± 12% µMol-min for the whole course, including outpatient doses. Additionally, the last 33 patients received venetoclax from days -22 to -3 in both arms. The GVHD prophylaxis was tacrolimus and mini-methotrexate in the first 29 patients and tacrolimus and cyclophosphamide in the remainder. The only difference between the two arms was if busulfan was started on day -20 or not. Results: A total of 116 patients were randomized, 59 to the shorter day -13 arm and 57 to the longer day -20 arm. Median age was 59 in the day -13 arm and 57 in the -20 arm. 70.7% had AML. 41.4% were transplanted in first complete remission. The characteristics of the two groups were well-balanced. The median follow-up in the 67 surviving patients was 48.9 months. More patients in the day -13 group experienced grade ≥3 toxicities than in the day -20 group (93.2% vs. 73.7%, p = 0.005). In particular, the incidence of grade ≥3 mucositis was significantly higher in the day -13 group compared to in the day -20 group (33.9% vs. 10.5%, p = 0.003), while there were no differences in the rates of grade ≥3 pneumonitis (18.6% vs. 7%, p = 0.1) and grade ≥3 sinusoidal obstruction syndrome (5.1% vs. 0%, p = 0.24) between the -13 and -20 arms. The difference in toxicity was associated with a reduction in the 3-year NRM in the -20 arm compared to the -13 arm (7% vs. 19%, p = 0.067). There was no difference in relapse rate (p = 0.99). The results of progression-free survival, overall survival, and GVHD-free relapse-free survival in the two groups are summarized in Table 1. Summary/Conclusion: Further fractionating busulfan and moving just one dose of busulfan 1 week earlier reduces toxicities and may lower NRM, without increasing relapse rate. ClinicalTrials.gov Identifier: NCT02250937.Keywords: Acute myeloid leukemia, Myelodysplastic syndrome, Busulfan